We propose to continue an integrated program of basic and clinical research to improve treatment of patients with acquired and inherited nonmalignant blood disorders and myelodysplastic syndromes by hematopoietic cell transplantation (HCT). The two clinical projects pursue two shared overall objectives for allogeneic HCT. One is to reduce conditioning-related toxicities and transplantation associated complications including graft rejection and graft-versus-host disease (GVHD). The other is to broaden the choice of hematopoietic cell donors beyond HLA-matched related and unrelated individuals by including grafts of HLA-haploidentical marrow cells and unrelated cord blood. The two preclinical projects will use a canine model with a long history of successful translation into clinical trials. One Project seeks to further improve major histocompatibility complex haploidentical HCT, in part by exploring combinations of biological and pharmacological immunosuppressive agents and in part by exploring novel post-transplantation chemotherapy strategies in combination with methods of transfer of drug resistance genes developed The other Project proposes to further optimize efficacy and safety of gene transfer into hematopoietic cells, test the therapeutic efficacy and safety of gene transfer in a clinically relevant canine inherited blood disorder, and study long-term consequences of gene transfer. The four research projects are supported by four core units, which provide study design, data processing, statistical analyses, protocol management, and coordination of multi-center trials, assessment of immune functions after transplantation, management of chronic GVHD,and long-term follow-up. The principles derived from the studies under this grant have had and will continue to have broad implications for marrow and blood stem cell transplantation and gene therapy in the treatment of patients with other malignant and nonmalignant blood disorders.